RU2012104856A - 3-PHENOXYMETHYLPYRROLIDINE COMPOUNDS - Google Patents

3-PHENOXYMETHYLPYRROLIDINE COMPOUNDS Download PDF

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RU2012104856A
RU2012104856A RU2012104856/04A RU2012104856A RU2012104856A RU 2012104856 A RU2012104856 A RU 2012104856A RU 2012104856/04 A RU2012104856/04 A RU 2012104856/04A RU 2012104856 A RU2012104856 A RU 2012104856A RU 2012104856 A RU2012104856 A RU 2012104856A
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hydrogen
compound according
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fluoro
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Эрик Л. СТЭНДЖЛЭНД
Дайсуке Роланд САИТО
Адам ХЬЮЗ
Джэйн ШМИДТ
ДАЙК Присцилла ВАН
Лори Джин ПАТТЕРСОН
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Тереванс, Инк.
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Abstract

1. Соединение формулы I:где Rвыбран из -Cалкила, -Cциклоалкила, необязательно замещенного 1 или 2 атомами фтора, -Cалкенила и -Cалкинила;R-Rнезависимо выбраны из водорода, галогена, -Cалкила, -CF, -O-Cлкила, -CN, -C(O)-Cалкила, -S-Cалкила, -Cциклоалкила и -NO; или Rи Rвзяты вместе с образованием -CH=CH-CH=CH-; или Rи Rвзяты вместе с образованием -CH-CH=CH-CH-;при условии, что когда Rпредставляет этил, Rпредставляет фтор-, Rпредставляет хлор-, Rпредставляет водород, и Rпредставляет водород, то Rне представляет фтор или хлор;или его фармацевтически приемлемая соль.2. Соединение по п.1, где Rпредставляет -Cалкил, выбранный из этила, пропила, изопропила, бутила, изобутила и 3-пентила.3. Соединение по п.1, где Rпредставляет -Cциклоалкил, необязательно замещенный 1 или 2 атомами фтора, выбранный из циклопропила, циклопентила, циклогексила и 4,4-дифторциклогексила.4. Соединение по п.1, где Rпредставляет бут-3-енил.5. Соединение по п.1, где Rпредставляет проп-2-инил.6. Соединение по п.1, где Rпредставляет водород, галоген, -Cалкил, -CF, -O-Cалкил, -C(O)-Cалкил, -S-Cалкил, -C-циклоалкил или -NO.7. Соединение по п.6, где Rпредставляет водород, фтор-, хлор-, -CH, -CHCH, -CF, -O-CH, -O-CHCH, -C(O)-CH, -S-CH, циклоалкил или -NO.8. Соединение по п.1, где Rпредставляет водород, галоген, -Cалкил, -CF, -O-Cалкил или -S-Cалкил.9. Соединение по п.8, где Rпредставляет водород, фтор-, хлор-, -CH, -CF, -O-CHили -S-CH.10. Соединение по п.1, где Rпредставляет водород, галоген, -Cалкил, -CFили -O-Cалкил.11. Соединение по п.10, где Rпредставляет водород, фтор-, хлор-, -CH, -CFили -O-CH.12. Соединение по п.1, где Rпредставляет водород, галоген, -Cалкил или -O-Cалкил.13. Соединение по п.12, где Rпредставляет водород, фтор-, хлор-, -CHили -O-CH.14. Соединение по п.1, где Rпредставляет водород, галоген или -Cалкил1. A compound of formula I: wherein R is selected from —Calkyl, —Cycloalkyl optionally substituted with 1 or 2 fluorine atoms, —Calkenyl and —Calkynyl; R — R are independently selected from hydrogen, halogen, —Calkyl, —CF, —O — Cl alkyl, - CN, -C (O) -Ci-alkyl, -S-Ci-alkyl, -C-cycloalkyl and -NO; or R and R are taken together with the formation of —CH═CH — CH═CH—; or R and R are taken together to form —CH — CH═CH — CH—; provided that when R is ethyl, R is fluoro, R is chloro, R is hydrogen, and R is hydrogen, then R is not fluoro or chloro; or a pharmaceutically acceptable salt. 2. A compound according to claim 1, wherein R 1 is -C-alkyl selected from ethyl, propyl, isopropyl, butyl, isobutyl and 3-pentyl. A compound according to claim 1, wherein R4 represents -Cycloalkyl optionally substituted with 1 or 2 fluorine atoms selected from cyclopropyl, cyclopentyl, cyclohexyl and 4,4-difluorocyclohexyl. A compound according to claim 1, wherein R1 represents but-3-enyl. The compound of claim 1, wherein R1 is prop-2-ynyl. 6. A compound according to claim 1, wherein R1 is hydrogen, halogen, —Calkyl, —CF, —O — C1-6alkyl, —C (O) —Calkyl, —S — C1-6alkyl, —C-cycloalkyl or —NO. The compound according to claim 6, where R is hydrogen, fluoro, chloro, —CH, —CHCH, —CF, —O — CH, —O — CHCH, —C (O) —CH, —S — CH, cycloalkyl or -NO.8. A compound according to claim 1, wherein R1 is hydrogen, halogen, —Calkyl, —CF, —O — C1-6alkyl or —S — C1-6alkyl. The compound of claim 8, wherein R1 is hydrogen, fluoro, chloro, —CH, —CF, —O — CH or —S — CH. A compound according to claim 1, wherein R1 is hydrogen, halogen, —Calkyl, —CF or —O — C1-6 alkyl. The compound of claim 10, wherein R1 is hydrogen, fluoro, chloro, —CH, —CF or —O — CH. A compound according to claim 1, wherein R1 is hydrogen, halogen, —Calkyl or —O — Calkyl. The compound of claim 12, wherein R1 is hydrogen, fluoro, chloro, —CH or —O — CH. The compound according to claim 1, where R represents hydrogen, halogen or -Cialkyl

Claims (31)

1. Соединение формулы I:1. The compound of formula I:
Figure 00000001
Figure 00000001
 где R1 выбран из -C2-6алкила, -C3-8циклоалкила, необязательно замещенного 1 или 2 атомами фтора, -C2-6алкенила и -C3-6алкинила;wherein R 1 is selected from —C 2-6 alkyl, —C 3-8 cycloalkyl optionally substituted with 1 or 2 fluorine atoms, —C 2-6 alkenyl, and —C 3-6 alkynyl; R2-R6 независимо выбраны из водорода, галогена, -C1-6алкила, -CF3, -O-C1-6лкила, -CN, -C(O)-C1-6алкила, -S-C1-6алкила, -C3-8циклоалкила и -NO2; или R4 и R5 взяты вместе с образованием -CH=CH-CH=CH-; или R5 и R6 взяты вместе с образованием -CH-CH=CH-CH-;R 2 —R 6 are independently selected from hydrogen, halogen, —C 1-6 alkyl, —CF 3 , —OC 1-6 alkyl, —CN, —C (O) —C 1-6 alkyl, —SC 1-6 alkyl, —C 3-8 cycloalkyl and —NO 2 ; or R 4 and R 5 are taken together to form —CH═CH — CH═CH—; or R 5 and R 6 are taken together to form —CH — CH═CH — CH—; при условии, что когда R1 представляет этил, R2 представляет фтор-, R4 представляет хлор-, R5 представляет водород, и R6 представляет водород, то R3 не представляет фтор или хлор;with the proviso that when R 1 is ethyl, R 2 is fluoro, R 4 is chloro, R 5 is hydrogen, and R 6 is hydrogen, then R 3 is not fluoro or chloro; или его фармацевтически приемлемая соль.or a pharmaceutically acceptable salt thereof. 2. Соединение по п.1, где R1 представляет -C2-6алкил, выбранный из этила, пропила, изопропила, бутила, изобутила и 3-пентила.2. The compound of claim 1, wherein R 1 is —C 2-6 alkyl selected from ethyl, propyl, isopropyl, butyl, isobutyl and 3-pentyl. 3. Соединение по п.1, где R1 представляет -C3-8циклоалкил, необязательно замещенный 1 или 2 атомами фтора, выбранный из циклопропила, циклопентила, циклогексила и 4,4-дифторциклогексила.3. The compound of claim 1, wherein R 1 is —C 3-8 cycloalkyl optionally substituted with 1 or 2 fluorine atoms selected from cyclopropyl, cyclopentyl, cyclohexyl and 4,4-difluorocyclohexyl. 4. Соединение по п.1, где R1 представляет бут-3-енил.4. The compound according to claim 1, where R 1 is but-3-enyl. 5. Соединение по п.1, где R1 представляет проп-2-инил.5. The compound according to claim 1, where R 1 represents prop-2-ynyl. 6. Соединение по п.1, где R2 представляет водород, галоген, -C1-6алкил, -CF3, -O-C1-6алкил, -C(O)-C1-6алкил, -S-C1-6алкил, -C3-8циклоалкил или -NO2.6. The compound according to claim 1, where R 2 represents hydrogen, halogen, -C 1-6 alkyl, -CF 3 , -OC 1-6 alkyl, -C (O) -C 1-6 alkyl, -SC 1- 6 alkyl, —C 3 - 8 cycloalkyl or —NO 2 . 7. Соединение по п.6, где R2 представляет водород, фтор-, хлор-, -CH3, -CH2CH3, -CF3, -O-CH3, -O-CH2CH3, -C(O)-CH3, -S-CH3, циклоалкил или -NO2.7. The compound according to claim 6, where R 2 represents hydrogen, fluoro, chloro, —CH 3 , —CH 2 CH 3 , —CF 3 , —O — CH 3 , —O — CH 2 CH 3 , —C (O) —CH 3 , —S — CH 3 , cycloalkyl or —NO 2 . 8. Соединение по п.1, где R3 представляет водород, галоген, -C1-6алкил, -CF3, -O-C1-6алкил или -S-C1-6алкил.8. The compound according to claim 1, where R 3 represents hydrogen, halogen, —C 1-6 alkyl, —CF 3 , —OC 1-6 alkyl, or —SC 1-6 alkyl. 9. Соединение по п.8, где R3 представляет водород, фтор-, хлор-, -CH3, -CF3, -O-CH3 или -S-CH3.9. The compound of claim 8, wherein R 3 is hydrogen, fluoro, chloro, —CH 3 , —CF 3 , —O — CH 3, or —S — CH 3 . 10. Соединение по п.1, где R4 представляет водород, галоген, -C1-6алкил, -CF3 или -O-C1-6алкил.10. The compound according to claim 1, where R 4 represents hydrogen, halogen, —C 1-6 alkyl, —CF 3 or —OC 1-6 alkyl. 11. Соединение по п.10, где R4 представляет водород, фтор-, хлор-, -CH3, -CF3 или -O-CH3.11. The compound of claim 10, wherein R 4 is hydrogen, fluoro, chloro, —CH 3 , —CF 3, or —O — CH 3 . 12. Соединение по п.1, где R5 представляет водород, галоген, -C1-6алкил или -O-C1-6алкил.12. The compound according to claim 1, where R 5 represents hydrogen, halogen, —C 1-6 alkyl or —OC 1-6 alkyl. 13. Соединение по п.12, где R5 представляет водород, фтор-, хлор-, -CH3 или -O-CH3.13. The compound of claim 12, wherein R 5 is hydrogen, fluoro, chloro, —CH 3 or —O — CH 3 . 14. Соединение по п.1, где R6 представляет водород, галоген или -C1-6алкил.14. The compound according to claim 1, where R 6 represents hydrogen, halogen or —C 1-6 alkyl. 15. Соединение по п.14, где R6 представляет водород, фтор-, хлор- или -CH3.15. The compound of claim 14, wherein R 6 is hydrogen, fluoro, chloro, or —CH 3 . 16. Соединение по п.1, где R5 и R6 взяты вместе с образованием -CH=CH-CH=CH-.16. The compound according to claim 1, where R 5 and R 6 taken together with the formation of -CH = CH-CH = CH-. 17. Соединение по п.1, где R2 и R3 представляют неводородные группы, а R4, R5 и R6 представляют водород.17. The compound according to claim 1, where R 2 and R 3 represent non-hydrogen groups, and R 4 , R 5 and R 6 represent hydrogen. 18. Соединение по п.1, где R2 и R4 представляют неводородные группы, а R3, R5 и R6 представляют водород.18. The compound according to claim 1, where R 2 and R 4 represent non-hydrogen groups, and R 3 , R 5 and R 6 represent hydrogen. 19. Соединение по п.1, где R3 и R4 представляют неводородные группы, а R2, R5 и R6 представляют водород.19. The compound according to claim 1, where R 3 and R 4 represent non-hydrogen groups, and R 2 , R 5 and R 6 represent hydrogen. 20. Соединение по п.1, где R2, R3 и R4 представляют неводородные группы, а R5 и R6 представляют водород.20. The compound according to claim 1, where R 2 , R 3 and R 4 represent non-hydrogen groups, and R 5 and R 6 represent hydrogen. 21. Соединение по п.1, где R2, R4 и R6 представляют неводородные группы, а R3 и R5 представляют водород.21. The compound according to claim 1, where R 2 , R 4 and R 6 represent non-hydrogen groups, and R 3 and R 5 represent hydrogen. 22. Соединение по п.1, которое представляет собой 3-[l-(4-хлорфенокси)-2-метилпропил]пирролидин.22. The compound according to claim 1, which is 3- [l- (4-chlorophenoxy) -2-methylpropyl] pyrrolidine. 23. Соединение по п.1, которое имеет конфигурацию, выбранную из:23. The compound according to claim 1, which has a configuration selected from:
Figure 00000002
Figure 00000002
Figure 00000003
Figure 00000003
 или обогащено стереоизомерной формой, имеющей такую конфигурацию.or enriched in a stereoisomeric form having such a configuration. 24. Соединение по п.23, которое выбрано из (R)-3-[(R)-1-(4-хлорфенокси)-2-метилпропил]пирролидина, (S)-3-[(S)-1-(4-хлорфенокси)-2-метилпропил]пирролидина, (S)-3-[(R)-1-(4-хлорфенокси)-2-метилпропил]пирролидина и (R)-3-[(S)-1-(4-хлорфенокси)-2-метилпропил]пирролидина.24. The compound according to item 23, which is selected from (R) -3 - [(R) -1- (4-chlorophenoxy) -2-methylpropyl] pyrrolidine, (S) -3 - [(S) -1- ( 4-chlorophenoxy) -2-methylpropyl] pyrrolidine, (S) -3 - [(R) -1- (4-chlorophenoxy) -2-methylpropyl] pyrrolidine and (R) -3 - [(S) -1- ( 4-chlorophenoxy) -2-methylpropyl] pyrrolidine. 25. Способ получения соединения по любому из пп.1-24, включающий снятие защиты с соединения формулы:25. A method of obtaining a compound according to any one of claims 1 to 24, including deprotecting a compound of the formula:
Figure 00000004
Figure 00000004
 где P представляет аминозащитную группу, с получением соединения формулы I или его соли.where P represents an amino protecting group to give a compound of formula I or a salt thereof. 26. Промежуточное соединение, пригодное в синтезе соединения по любому из пп.1-24, имеющее формулу:26. An intermediate compound useful in the synthesis of a compound according to any one of claims 1 to 24, having the formula:
Figure 00000005
Figure 00000005
 где P представляет аминозащитную группу.where P represents an amino protecting group. 27. Фармацевтическая композиция, содержащая соединение по любому из пп.1-24 и фармацевтически приемлемый носитель.27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24 and a pharmaceutically acceptable carrier. 28. Фармацевтическая композиция по п.27, дополнительно содержащая второе терапевтическое средство, выбранное из средств против болезни Альцгеймера, противосудорожных средств, антидепрессантов, средств против болезни Паркинсона, двойных ингибиторов обратного захвата серотонина-норэпинефрина, нестероидных противовоспалительных средств, ингибиторов обратного захвата норэпинефрина, опиоидных агонистов, селективных ингибиторов обратного захвата серотонина, блокаторов кальциевых каналов, симпатолитиков и их комбинаций.28. The pharmaceutical composition according to item 27, additionally containing a second therapeutic agent selected from anti-Alzheimer's disease, anticonvulsants, antidepressants, anti-Parkinson’s drugs, double serotonin-norepinephrine reuptake inhibitors, non-steroidal anti-inflammatory drugs, norepinephrine reuptake inhibitors, agonists, selective serotonin reuptake inhibitors, calcium channel blockers, sympatholytics, and combinations thereof. 29. Соединение по любому из пп.1-24 для применения при лечении.29. The compound according to any one of claims 1 to 24 for use in treatment. 30. Соединение по п.29 для лечения болевых расстройств, депрессивных расстройств, аффективных расстройств, гиперактивных расстройств с дефицитом внимания, когнитивных расстройств, стрессового недержания мочи, синдрома хронической усталости, ожирения и вазомоторных симптомов, связанных с менопаузой.30. The compound according to clause 29 for the treatment of pain disorders, depressive disorders, affective disorders, attention deficit hyperactive disorders, cognitive disorders, stress urinary incontinence, chronic fatigue syndrome, obesity and vasomotor symptoms associated with menopause. 31. Соединение по п.30, где болевое расстройство представляет собой нейропатическую боль, фибромиалгию или хроническую боль. 31. The compound of claim 30, wherein the pain disorder is neuropathic pain, fibromyalgia, or chronic pain.
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